Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

Functionalized tetrahydropyran (THP) rings are important building blocks and ubiquitous scaffolds in many natural products and active pharmaceutical ingredients (API). Among various established methods, the Prins reaction has emerged as a powerful technique in the stereoselective synthesis of the tetrahydropyran skeleton with various substituents, and the strategy has further been successfully applied in the total synthesis of bioactive macrocycles and related natural products. In this context, hundreds of valuable contributions have already been made in this area, and the present review is intended to provide the systematic assortment of diverse Prins cyclization strategies, covering the literature reports of the last twenty years (from 2000 to 2019), with an aim to give an overview on exciting advancements in this area and designing new strategies for the total synthesis of related natural products.


Introduction
6-Membered saturated oxygen heterocycles, known as tetrahydropyran (THP), are recognized as privileged scaffolds, present in a variety of biologically important natural products, such as polyether antibiotics, marine toxins, pheromones, and pharmaceutical agents. These structural motifs are frequently used as synthons and as key intermediates for natural product synthesis. Therefore, the development of stereoselective synthetic methods for the substituted THP subunit has long been the area of fundamental research in organic chemistry. Thus far, several methods have been devised for the construction of substituted tetrahydropyran rings. Since the year 2000, a number of conceptually different reactions have been developed for the efficient construction of THP rings and were eventually employed in the total synthesis of natural products [1][2][3][4][5][6][7][8]. Prins and related cyclization reactions [9,10], hetero-Diels-Alder cyclization [11], cyclization onto epoxides [12], Petasis-Ferrier rearrangement [13], intramolecular oxa-Michael reactions [14], cyclization through oxidative C-H bond functionalization [15], ring-closing metathesis (RCM) [16], halo etherification [17], reductive etherification [18,19], and metal-mediated cyclization [20,21], etc. are the most frequent strategies utilized for THP ring construction (Scheme 1). Amongst all, the Prins reaction has proven as a powerful technique in the stereoselective synthesis of the THP key scaffold and its application towards the total synthesis of natural products. Many advancements were also taking place in Prins cyclization methodologies over that period of time. This appraisal aims to bring together the work of many research groups in the area of the development of Prins and related cyclization strategies along with the discussion on the general mechanistic part. We sincerely hope that this review will deliver a snapshot of the up-to-date state of the inventiveness in this field, and most importantly, it will give an inspiration to the reader to take up the challenge and contribute greater advances in this area in the future. This review comprises the literature reports over the last twenty years and its advances. It is likely that some references may have escaped our attention unintentionally, for which we would greatly apologize to those whose contribution in this area has not been included.

Review Prins cyclization: general
For the first time, in 1899, Kriewitz [22] reported the synthesis of unsaturated pinene alcohol through a thermal ene reaction using β-pinene and paraformaldehyde. After nearly twenty years, Prins explored this reaction further for the synthesis of diol by the condensation of styrene and paraformaldehyde in the presence of a Brønsted acid [23,24]. The major breakthrough for this reaction was reported by Hanschke in 1955, when the THP ring was selectively constructed through a Prins reaction involving 3-butene-1-ol and a variety of aldehydes or ketones in the presence of acid (Scheme 2) [25]. Although the Kriewitz reaction was an ene reaction, the mechanism of the reaction was described to proceed via an oxocarbenium ion intermediate captured by a π-nucleophile, followed by the addition of an external nucleophile, leading to the formation of products. Since then, the Prins cyclization emerged as the most commonly used strategy for the stereoselective construction of the THP ring, and its application lead to some excellent reviews on the Prins reaction [26,27]. In general, an endo cyclization proceeds via an oxocarbenium ion intermediate in a stereoselective manner for THP ring formation as shown in Scheme 3.
The outcome of exclusive cis-stereoselectivity in the Prins cyclization might be attributed to the most favorable conformation adopted by 12 with equatorial orientation of the 2,6-substituents (R 1 and R 2 ). Alder and co-workers explained the formation of all-cis-2,4,6-trisubstituted THPs with the help of density functional theory (DFT) and stated that in the presence of an external nucleophile, the stabilization of the carbocation intermediate is favored through hyperconjugation [28]. The vacant p-orbital of C4 in TS 12a overlaps efficiently with the HOMO of the incoming nucleophile in an equatorial attack. Furthermore, this pseudoaxial C4 hydrogen atom in TS 12a leads to an optimal overlap between σ and σ* of C2-C3 and C5-C6 with the coplanar equatorial lone pair of the oxygen atom and the empty p-orbital at C4. These orbital stabilizations, along with the lack of 1,3-diaxial interaction experienced by the incoming nucleophile (mostly halide) leads to the preferential equatorial attack over an axial attack by the nucleophile (Scheme 3) to give all-cis-2,4,6-trisubstituted THPs. In the absence of an external nucleophile, the successive proton loss leads to the formation of the 2,6-disubstituted dihydropyran. The regioselectivity of the Prins reaction is explained through the intermediates formed during the course of the reaction (Scheme 4). The Z-homoallylic alcohol reacts with an activated aldehyde to give oxocarbenium ion 15, wherefrom two competing transition states, 15a and 15b, can possibly form. In the 6-membered chair-like transition state 15a, there is a 1,3-diaxial interaction between "H" and the substituent R 2 , while for the other fivemembered transition state 15b, there is no such 1,3-diaxial interaction, which favors the formation of tetrahydrofuran product 17 instead of the tetrahydropyran 16 (Scheme 4).
Although the Prins cyclization is one of the powerful tools for the construction of 2,6-disubstituted THPs, there are some limitations that restrict a wide applicability. The major drawbacks identified with the Prins cyclization are the racemization due to competing oxonia-Cope rearrangement and sidechain exchange. Willis and co-workers studied the reactivity of the Prins reaction of different aryl group-substituted homoallylic alcohols 18 with propanal in the presence of a Lewis acid, which furnished the expected tetrahydropyran 23 as a single diastereomer via an oxocarbenium intermediate 21 (Scheme 5) [29,30].
The reaction was dependent from the nature of the aromatic ring, which plays a crucial role in the product formation. Homoallylic alcohols with an electron-rich substituent at the arene ring produced predominantly symmetric THP product 26 over the desired trisubstituted heterocycle 23. The mechanism Scheme 4: Regioselectivity in the Prins cyclization. of the reaction was further investigated using enantioenriched homoallylic alcohol (S)-18 with 89% ee, which favored 2-oxonia-Cope rearrangement to give THP 23 only in 14% yield and <5% ee. The poor enantiomeric excess of the product 23 indicates that the racemization takes place during the course of the reaction. It was explained that the reason for the loss of optical purity was due to the formation of a benzylic cation, which is stabilized by the electron-rich aromatic substituent. In contrast, the reaction with aromatic aldehydes equipped with the electron-deficient substituent produced the desired trisubstituted THP along with recovered starting material. The enantioenriched homoallylic alcohol bearing an electron-deficient substituent, 27 (94% ee), was investigated with propanal, which proceeded with high selectivity to give the corresponding THP 28 (79% ee, 32% yield) along with some recovered starting material (47%), as shown in Scheme 6. Partial racemization was also reported at the same time by reversible 2-oxonia-Cope rearrangement and via side-chain exchange [31][32][33]. The racemization occurs during allyl transfer as a result of 2-oxonia-Cope rearrangement through a 3,3sigmatropic shift, which plays a crucial role during the reaction, as shown in Scheme 7. The Prins cyclization between alcohol (R)-35 and aldehyde 36 was investigated under different Lewis acid conditions, as shown in Scheme 8 [33]. Cyclization promoted by BF 3 ·OEt 2 / HOAc led to partial racemization of the desired product 37 (from 87% ee to 68% ee) and formation of side-chain exchange products 38 and 39 (symmetric tetrahydropyran). Presumably, this observation stands in support of the intervention of a 2-oxonia-Cope-mediated side-chain exchange reaction and is entirely consistent with Willis and co-workers' result [29], which leads to the partial racemization observed in the desired product formation. Another Lewis acid, SnBr 4 , was found to be more efficient than BF 3 ·OEt 2 /HOAc in terms of retention of enantiopurity in major product 37 during cyclization (from 87% ee to 85% ee, Scheme 8). This could probably be due to a faster rate of cyclization with SnBr 4 , which suppressed the competing 2-oxonia-Cope process.
In order to stop racemization during the Prins cyclization, a substrate in which an oxocarbenium ion is generated from a masked aldehyde bearing a homoallylic alcohol moiety has been examined. In this context, the α-acetoxy ethers with different functionalities at C4 were examined in the presence of a variety of Lewis acids, and it was found that the α-acetoxy ether (R)-42 underwent Prins-type cyclization in the presence of BF 3 ·OEt 2 as well as SnBr 4 to deliver the desired 37 and 40, respectively, without loss of optical purity (Scheme 9) [34,35].
This strategy was successfully utilized for the synthesis of the natural product (−)-centrolobine [33] and for the stereoselective synthesis of the C20-C27 tetrahydropyran segment of phorboxazole A (Scheme 10) [36].

Axial selectivity in the Prins cyclization
To overcome the racemization process, the axially selective Prins cyclization was explored with a variety of substrates,  which produced the corresponding THPs in excellent selectivity and good to excellent yield [37]. The experimental modification under segment coupling gave entirely the 4-axial product. For example, treatment of 47 with SnBr 4 produced axial and equatorial products 48a and 48b in a 9:79 ratio under typical segment coupling. This selectivity was further improved for the formation of 48a by exclusively using TMSBr as a Lewis acid, as shown in Scheme 11.
The mechanistic rationale for an axially selective Prins cyclization is explained in Scheme 12 [38]. It is proposed that the reaction of 49 with TMSBr forms an intermediate 50, which, after solvolysis, affords an intimate ion pair 51. The proximal addition of a bromide ion to 51 produces axial adduct 56 exclusive-ly. However, when SnBr 4 is used as a Lewis acid, oxocarbenium ion 52 is formed via 50. The counterion SnBr 4 − being much less nucleophilic than the Br − ion allows the formation of a solvent-separated ion pair 53, which results in the bromide addition to 53 preferentially from an equatorial position (Scheme 12).

Mukaiyama aldol-Prins cyclization
The Mukaiyama aldol-Prins (MAP) cyclization has also been explored for the synthesis of tetrahydropyran. In this approach, the side reaction is avoided by introducing a nucleophile into the enol ether, which traps the reactive oxocarbenium ion intermediate 60, leading to the formation of THP [39]. The first example of an MAP cascade reaction was reported by Rych-Scheme 13: Mukaiyama aldol-Prins cyclization reaction.

Scheme 14:
Application of the aldol-Prins reaction.
novsky and co-workers using allylsilane 62 as an internal nucleophile, as shown in Scheme 13 [40].
This approach was further extended to the synthesis of the macrolide lecasacandrolide A [41]. BF 3 ·OEt 2 in combination with 2,6-di-tert-butylpyridine (DTBP) was a suitable combination for the synthesis of the THP unit of leucasacandrolide A, while TiBr 4 [42] was found suitable in conjunction with DTBP for the synthesis of polyketide SCH 351448 [43], as shown in Scheme 14. Hart and Bennett have also examined the trifluroacetic acid-catalyzed Prins cyclization of acetal 71 to afford 72 along with side-chain-exchanged product 73 (Scheme 15) [44].
This method was utilized for the synthesis of (−)-blepharocalyxin D29 [45] and the macrolide leucascandrolide A [46]. In another type, the triflic acid-catalyzed Prins cyclization was used for the synthesis of 2,4,5,6-tetrasubstituted tetrahydropyran with complete control of stereochemistry, which is an important core of a variety of natural products, such as polycarvernoside A [47], clavoslide A [48], and (−)-blepharocalyxin [49,50] and its analogs, as shown in Scheme 16.
Additionally, the reaction was used for the synthesis of rhoiptelol B, 7-desmethoxyfusarentin, and corresponding analogs [51]. Considering β-hydroxydioxinone as a better starting material for Prins cyclization, Scheidt and co-workers introduced a new method to access highly functionalized chiral THP efficiently (Scheme 17) [52].
Furthermore, the possible reaction pathway indicates the formation of oxocarbenium ion 82, followed by C-C bond formation via a chair-like transition state to afford 83 (Scheme 18). A se-quence of reactions involving elimination of a proton from 83, treatment of 84 with an alkoxide, and protonation of the resulting enolate delivered thermodynamically favored equatorial ester 80 and 81.
Funk and Cossey demonstrated that ene-carbamate could be an excellent terminating group for Prins cyclization [54]. The reaction involved 87 in the presence of the mild Lewis acid InCl 3 and benzaldehyde (88), which produced all-cis-tetrahydropyran-4-one 90 in excellent yield. The transformation proceeded through cyclization of a diequatorial chair-like conformation of the oxocarbenium ion 89 to provide an N-acyliminium ion, which upon hydrolysis produced 90. Similarly, the reaction of 91 produced all-cis-2,3,6-trisubstituted tetrahydropyran 93. The application of this reaction was further extended by an exceptionally concise formal total synthesis of the nuclear export inhibitor (+)-ratjadone A, as shown in Scheme 20.
Scheme 18: Mechanism for the Lewis acid-catalyzed synthesis of tetrahydropyran-4-one.
Stereoselective Prins cyclization of substituted cyclopropylcarbinol 94 to 2,4,6-trisubstituted tetrahydropyran 97 was reported by Yadav and Kumar [55]. In this reaction, a homoallylic cation was generated from 94 by the opening of the cyclopropane ring in the presence of TFA, which upon reacting with an aldehyde delivered 2,4,6-trisubstituted tetrahydropyran 97 through Prins cyclization, as shown in Scheme 21.
Similarly, an SnCl 4 -catalyzed Prins reaction was reported for the synthesis of 4-chlorotetrahydropyran 100. This intermediate was further utilized for the synthesis of the natural product centrolobine, as shown in Scheme 22 [56].
In continuation, 4-amidotetrahydropyran derivative 106 was also synthesized from homoallylic alcohol 104 and an aldehyde 105 using a combination of cerium chloride and acetyl chloride following a Prins-Ritter reaction sequence (Scheme 24) [58]. 10 mol % cerium chloride was used as a reaction promotor, which dramatically improved the reaction rate and yield of the reaction. In a related study, the synthesis of polysubstituted tetrahydropyrans was described by Amberlyst ® 15-catalyzed cyclization of homoallyl alcohol 107 and aldehydes 108. This method was further employed for the synthesis of highly substituted tetrahydropyrans with three contiguous stereocenters in one single operation [59]. The utility of this approach is showcased in the enantioselective total synthesis of (+)-prelactones B, C, and V, as shown in Scheme 25.
Scheme 25: Yadav and co-workers' strategy to prelactones B, C, and V.
Yadav's group reported the synthesis of 4-iodotetrahydropyrans (dr = 7.5:2.5) from aromatic aldehyde 111 and homoallylic alcohol 110 using TMSCl and NaI. Furthermore, the major diastereomer was utilized for the synthesis of centrolobine, as shown in Scheme 26 [60].
Loh and co-workers have shown the construction of cis-2,6disubstituted tetrahydropyran 116 with an exocyclic double bond by reacting homoallylic alcohol 114 and aldehyde 115 in the presence of a catalytic amount of In(OTf) 3 [61]. This approach was further used for the synthesis of a common intermediate 117 for (−)-zampanolide and (+)-dactyloide (Scheme 27) [62].
Further improvement of this reaction was achieved by carrying out the Prins cyclization between homoallyl alcohol 118 (or Scheme 27: Loh and co-workers' strategy for the synthesis of zampanolide and dactylolide.

Scheme 28:
Loh and Chan's strategy for THP synthesis.
using the corresponding aldehyde and allylsilyl chloride 119) and an aldehyde 120 in the presence of a catalytic amount of the mild Lewis acid In(OTf) 3 and trimethylsilyl halide as an additive to produce cis-4-halo-2,6-disubstituted tetrahydropyran 121 (Scheme 28) [63,64]. It was noticed that the problem associated with epimerization of the substrate has been successfully overcome in this reaction, which was demonstrated in the enantioselective total synthesis of (−)-centrolobine using catalytic InBr 3 as a mild Lewis acid.

Silyl-Prins cyclization
Extensive research efforts were made towards the synthesis of THP using the silyl-Prins cyclization reaction. In this reaction, an oxocarbenium ion is being trapped by allylsilanes, vinylsilanes, alkenyl methylsilanes, or propargylsilanes to produce a variety of the Prins-cyclized products. The allyl metalation, followed by intramolecular Sakurai cyclization (IMSC) provides an efficient route to a variety of tetrahydropyran derivatives, as described by Marko and Leroy [68,69]. In these approaches, an initial ene reaction between an aldehyde 139 and the allylsilane 138 was promoted by Et 2 AlCl to generate Z-configured homoallylic alcohol 140. Condensation of 140 with another aldehyde in the presence of BF 3 ⋅OEt 2 afforded the polysubstituted exo-methylene tetrahydropyran 142 in a completely stereocontrolled manner. The reaction proceeded via oxocarbenium 141, which upon intramolecular trapping by the allylsilane moiety through a chair-like transition state delivers the product (Scheme 33) [68].
An analogous reaction was reported between (E)-enol carbamate 143 and an aldehyde 144 in the presence of BF 3 ·OEt 2 to provide THP 146 with exquisite diastereoselectivity. The carbamate substituent adopted the axial disposition in the proposed transition state 145, as shown in Scheme 34 [69].

Scheme 32:
Martín and co-workers' stereoselective approach for the synthesis of highly substituted tetrahydropyrans through an Evans aldol−Prins cyclization strategy. In another report by Rychnovsky and Gisinsky, two of the tetrahydropyran rings of the potent molluscicide cyanolide A were synthesized via a silyl-Prins cyclization and Sakurai macrocyclization/dimerization strategy to produce 150 in the presence of TMSOTf, as shown in Scheme 35 [70].

Tandem allylation-silyl-Prins cyclization
Tetrahydropyran can also be synthesized stereoselectively by sequential allylation to an aldehyde, followed by silyl-Prins cyclization of the resulting homoallylic alcohol. For illustration, a facile enantioselective strategy for the synthesis of cis-2,6-disubstituted 4-methylenetetrahydropyran 161 (91% yield, dr = 5:1) was reported by Yu et al, utilizing, first, asymmetric allylation of an aldehyde by using [{(R)-BINOL}Ti(IV){OCH(CF 3 ) 2 } 2 ] as a chiral promotor in PhCF 3 , followed by cyclization using R 2 CHCl(OMe) in the presence of TMSNTf 2 , as shown in Scheme 38 [73]. The internal chirality transfer during cyclization probably took place due to the geometrical preference of 162 to minimize the allylic strain with the existing stereogenic center (pseudoaxial group), leading to the formation of cis-tetrahydropyran 161 rather than a transtetrahydropyran. Floreancig and co-workers utilized a tandem allylation-silyl-Prins cyclization strategy to afford 2,6-disubstituted tetrahydropyran 167 by ionizing α,β-unsaturated acetals 164 in the presence of electron-rich olefins using Ce(NO 3 ) 3 and SDS in water [74]. The mechanism of the reaction is shown in Scheme 39, which plausibly proceeded through trapping of oxocarbenium ion 166 in a chair-like transition state.
The stability of the acetal under these reaction conditions reflected that the acid-sensitive functional groups are well tolerated in the cyclized product. Furthermore, a natural product, (+)-dactyloide, was synthesized by following the above strategy using an appropriate acetal (Scheme 40) [75]. In contrast, the reaction of anti-170 proceeded, however, through similar boat-like transition states 176 and 177 where the interaction between the methyl substituent and the alkyl group of aldehyde was less, leading to the formation of trans,trans-178 as a major product, as shown below in Scheme 43.
This strategy was further utilized for the synthesis of the C29−C45 bispyran subunit (E−F) of spongistatin [82]. 2,6-Disubstituted 4-methylenetetrahydropyran was also synthesized from silylstannane and two units of aldehyde in a two-step protocol. The first step involves the addition between silylstan-Scheme 44: Roush and co-workers' [4 + 2]-annulation strategy for DHP synthesis [82].
Unlike allyl-and vinylsilanes, as discussed earlier, Furman and co-workers introduced a new concept of synthesizing 211 utilizing silyl-Prins cyclization of propargylsilane 209 and aldehyde 210 in the presence of TMSOTf [93]. The oxocarbenium ion was intramolecularly trapped by the olefin, followed by removal of trimethylsilane (Scheme 50).
The authors further explored this strategy for the asymmetric synthesis of 3-vinylidene-substituted tetrahydropyran by taking the chiral propargylsilane. A diastereoselective route to cis-2,6disubstituted tetrahydropyran-4-one 215 was explored by introducing a silyl enol ether Prins cyclization concept in which Scheme 52: Rychnovsky and co-workers' strategy for THP synthesis from hydroxy-substituted silyl enol ethers. oxocarbenium ion 214, generated by reacting hydroxy-substituted silyl enol ether 212 with aldehyde 213 (different types of aliphatic and aromatic as well as α,β-unsaturated aldehydes were used), was trapped by silyl enol ether [94]. A detailed mechanism similar to simple Prins cyclization, except trapping of oxocarbenium ion 214 with silyl enol ether instead of olefin, vinylsilane, or allylsilanes, was proposed as shown in Scheme 51.

Scheme 51: THP synthesis from silyl enol ethers.
However, the reaction of silyl enol ether such as 216, upon reacting with an unsaturated aldehyde 217, produced a mixture of cis-and trans-220 (dr = 4.1:1.0). It was explained that the diastereoselectivity of the product depends on the size of the substituent. For example, when the substituent is sterically small, it occupies the pseudoaxial position in the reactive conformation 218 (Scheme 52).
Li et al. utilized allylic geminal bissilyl alcohol 221 for the construction of THP ring A of (−)-exiguolide via Prins cyclization with an aldehyde in the presence of Lewis acid as a promoter [95]. High yield and excellent diastereoselectivity were obtained under standard silyl-Prins cyclization conditions using TMSOTf as Lewis acid (Scheme 53). Recently Xu et al. reported the homoallylic silyl alcohol 224 containing a multisubstituted (Z)-alkene reacting with an aldehyde in the presence of TMSI and InCl 3 to afford 226 in high diastereoselectivity [96]. The authors assumed that the Prins cyclization proceeded through Alder's chair-like transition state 227 in which the (Z)-alkene accounts for the trans-stereocontrol at the C3 position and equatorial iodide addition accounts for the cis-stereocontrol at the C4 position, as shown below in Scheme 54.
The one-pot synthesis of tetrahydropyran by utilizing the Babier-Prins cyclization reaction of allyl bromide (228) with a carbonyl compound promoted by BBIMBr/SnBr 2 complex under solvent-free conditions has been explored [97]. The mechanism of the reaction was shown to include a Barbier reaction of allyl bromide with an aldehyde in the presence of SnBr 3 and a quaternary ammonium salt to produce allyltin compound 230, which subsequently reacts with an aldehyde to generate intermediate 231. This intermediate could be hydrolyzed by water during workup to afford 232, which does not give the required THP product. Desired product 235 was obtained only in the anhydrous conditions (Scheme 55).

Scheme 55:
Wang and co-workers' strategy for tetrahydropyran synthesis.
Scheme 57: Martín, Padrón, and co-workers' proposed mechanism of alkynylsilane Prins cyclization for the synthesis of DHP. From DFT calculations, the authors concluded that the Prins product is formed more rapidly than the α-trimethylsilylalkenyl cation 242 formed by the Grob-type fragmentation (Scheme 57), which was trapped by the subsequent attack of the halide anion, leading to the formation of Prins product 244. On the basis of theoretical calculations, the authors could conclude factors controlling the alkyne Prins cyclization over formal 2-oxonia- [3,3]-sigmatropic rearrangement.
Furthermore, Markó and co-workers successfully synthesized 2,6-anti-configured THP starting from allylsilane 245, following diethylaluminium chloride-promoted ene reaction and condensation with an aldehyde 246 [102]. Expected ene adduct 247 was obtained as a (Z)-olefin. The addition of ZnCl 2 ·Et 2 O and (MeO) 3 CH to the resulting homoallylic alcohol 247 leads to the desired pyran derivative 248, having an acetal group at the C2 position (Scheme 58). By treatment of acetal 248 with allyltrimethylsilane gave 2,6-anti-configured THP 249 as a single diastereomer in the presence of TMSOTf.
Scheme 60: Loh and co-workers' strategy for anti-THP synthesis.
The possible mechanism for the formation of a variety of isomers was explained through transition state 254 and 255 (Scheme 60). Competition between electronically favored transition state 254 leads to the formation of anti-isomer 256, whereas the sterically preferred transition state 255 afforded syn-isomer 257.
Unlike the well-explored selective synthesis of major cis-2,6-THP, a highly stereoselective route to the thermodynamically disfavored trans-2,6-tetrahydropyran 260 was reported by Cha and co-workers based on the coupling of hydroxyethyl-tethered cyclopropanol 258 and aliphatic aldehyde 259 using TiCl 4 as a Lewis acid [104,105]. The reaction proceeded through the Prins cyclization (Scheme 61).
The reaction proceeded via formation of a 7-membered cyclic acetal 263 as a single isomer in nearly quantitative yield, followed by Lewis acid-catalyzed rearrangement leading to the Scheme 61: Cha and co-workers' strategy for trans-2,6-tetrahydropyran.
formation of tetrahydropyran. Under optimized reaction conditions, TMSOTf gave 7-membered cyclic acetal 263, which upon treatment with TiCl 4 gave the desired THP as a 14:1 mixture of trans-and cis-265 in 80% yield. The trans-265 was obtained as a major isomer, where the reaction proceeded through the 6-membered chair-like transition state 264, and the electrophilic ring opening of cyclopropane by the oxocarbenium ion was believed to proceed via "corner attack" at the less substituted C-C bond. However, minor cis-265 was formed via the 6-membered boat like transition state 264' (Scheme 62) [104]. Cha's group also utilized the Rechnovsky convergent method where an α-acetoxy ether was used as a precursor for the oxocarbenium ion in the THP synthesis to complement the aforementioned 7-membered cyclic acetal strategy. The treatment of α-acetoxy ether 266 with Lewis acid produced the corresponding THP 267 with moderate diastereoselectivity in favor of the trans-2,6-stereoisomer, as shown in Scheme 63. The authors proposed fundamental insights into the mechanism of the reaction based on DFT calculations. A different [2 + 2]-cycloaddition process was suggested to rationalize the observed OH-selectivity.
In 2015, Padrón and co-workers also reported the Prins cyclization catalyzed by a Fe(III) and trimethylsilyl halide system for the synthesis of all-cis-2,4,6-trisubstituted THP [107]. As reported previously by Feng et al. [106], two mechanistic pathways via the classical oxocarbenium route and [2 + 2]-cycloaddition were considered for DFT calculations. Experimental and DFT studies suggested the preference of a classical oxocarbenium route over the [2 + 2]-pathway for those alcohols having unactivated and unsubstituted alkenes, whereas the substituent adjacent to the hydroxy group in the homoallylic alcohol A series of geminal bishalogen-containing fused THPs was synthesized in high yield (up to 80%) and excellent diastereoselectivity. A Prins cyclization mechanism was proposed for the above transformation in the presence of TiCl 4 . Formation of the oxocarbenium ion 289, followed by an intramolecular nucleophilic attack by the alkynyl bond on the cyclopropane unit gave cyclic oxocarbenium intermediate 290. Further, the attack of a halide anion (from TiX 4 ) leads to the Prins cyclization to give bishalogenated bicyclic THP with all-cis-stereochemistry in the major product.

Asymmetric Prins cyclization
Mullen and Gagné reported a first catalytic asymmetric Prins cyclization reaction between 2-allylphenol 292 and glyoxylate ester 293 using (R)-[(tolBINAP)Pt(NC 6 F 5 ) 2 ][SbF 6 ] 2 (294) as chiral catalyst [110]. An optimization study revealed that the enantioselectivity varied with the polarity of the solvent. The optimization study disclosed that the enantioselectivity increases with the decrease of the polarity of the solvent (Scheme 68).
Yu and co-workers reported a novel segment-coupling Prins cyclization involving sequential benzylic/allylic C-H bond activation via DDQ oxidation, followed by nucleophilic attack of an unactivated olefin to obtain all-cis-trisubstituted Prins products with high stereochemical precision [111]. A single-electron transfer (SET) mechanism was proposed for the above transformation (Scheme 69). A SET from an arene or alkene to DDQ and the subsequent abstraction of hydride from the benzylic or allylic position generated a charge-transfer complex 298. The complex 298 formed a tin-containing ate oxocarbenium ion complex 299 with SnBr 4 , and then rapid C-C bond formation took place to generate the cyclic intermediate 300.
Lalli and van de Weghe reported a chiral BINOL-derived bisphosphoric acid-and CuCl-catalyzed enantioselective tandem Prins-Friedel-Crafts cyclization between homoallylic alcohol 302 and substituted aromatic aldehydes 303 to form hexahydro-1H-benzo[f]isochromenes 305 with three new contiguous stereocenters in high enantio-and diastereoselectivity [112]. The three new contiguous stereogenic centers formed resulted from an attack of the alkene to the Si-face of the oxocarbenium ion, which was followed by a completely diastereoselective Friedel-Crafts reaction (Scheme 70).
List and co-workers devised a strategy employing highly acidic confined iminoimidodiphosphate (iIDP) Brønsted acids 308 that catalyzed asymmetric Prins cyclizations of both aliphatic and aromatic aldehydes with alcohol 307 to obtain 309 (Scheme 71) [113]. The introduction of electron-withdrawing nitro groups on the BINOL backbone in the catalysts significantly enhanced the reactivity and enantioselectivity. Zhou et al. reported an asymmetric Prins cyclization of in situgenerated quinone methides from phenol-tethered alkenyl alcohol 310 and o-aminobenzaldehyde 311 using chiral phosphoric acids (Scheme 72) [114]. Diverse functionalized transfused pyranotetrahydroquinoline derivatives 312 were synthesized in excellent yield and selectivity (up to 99% yield and 99% ee). List et al. reported a chiral imidodiphosphoric acid-catalyzed asymmetric Prins cyclization with salicylaldehyde 316 and 3-methylbut-3-en-1-ol (317) to afford 4-methylenetetrahydropyrans 318 with high enantioselectivity (Scheme 73) [115]. A chiral bis-BINOL-based imidophosphoric acid 319 was efficient in this reaction, and the extreme bulkiness of this catalyst was the key to a successful transformation. This reaction proceeded via a Prins cyclization mechanism, activated by chiral acid 319.

Conclusion
Prins cyclization strategies have been proven as a reliable and robust method for the stereoselective construction of THP rings. Many of these strategies have been utilized for the elegant synthesis of natural products. In this review, we portrayed an inspection of twenty years in the arena of the development of Prins cyclizations and the further exploration of these strategies in the total synthesis of natural products. This up-to-date information showcases the knowledge gained in this area. In either Scheme 73: List and co-workers' approach for asymmetric Prins cyclization using chiral imidodiphosphoric acid 319.
case, it is hoped that the challenge of stereoselective construction of THP rings in the context of natural product synthesis will continue to inspire synthetic chemists to develop new methods in the coming years.